Dataset Information

Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14.

ABSTRACT: Distal hereditary motor neuronopathy type VII (dHMN-VII) is an autosomal dominant disorder characterized by distal muscular atrophy and vocal cord paralysis. We performed a genomewide linkage search in a large Welsh pedigree with dHMN-VII and established linkage to chromosome 2q14. Analyses of a second family with dHMN-VII confirmed the location of the gene and provided evidence for a founder mutation segregating in both pedigrees. The maximum three-point LOD score in the combined pedigree was 7.49 at D2S274. Expansion of a polyalanine tract in Engrailed-1, a transcription factor strongly expressed in the spinal cord, was excluded as the cause of dHMN-VII.

SUBMITTER: McEntagart M

PROVIDER: S-EPMC1226107 | biostudies-literature | 2001 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14.

McEntagart M M Norton N N Williams H H Teare M D MD Dunstan M M Baker P P Houlden H H Reilly M M Wood N N Harper P S PS Futreal P A PA Williams N N Rahman N N

American journal of human genetics 20010404 5

Distal hereditary motor neuronopathy type VII (dHMN-VII) is an autosomal dominant disorder characterized by distal muscular atrophy and vocal cord paralysis. We performed a genomewide linkage search in a large Welsh pedigree with dHMN-VII and established linkage to chromosome 2q14. Analyses of a second family with dHMN-VII confirmed the location of the gene and provided evidence for a founder mutation segregating in both pedigrees. The maximum three-point LOD score in the combined pedigree was 7 ...[more]

PMID: 11294660

Similar Datasets

Project description:Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases, with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild-type full-length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic Caenorhabditis elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress, which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.

Dataset Information

Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14.

Publications

Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets